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Abstract:

A particulate SAE-CD composition is provided. The SAE-CD composition has
an advantageous combination of physical properties not found in known
solid forms of SAE-CD. In particular, the SAE-CD composition possesses an
advantageous physicochemical and morphological property profile such that
it can be tailored to particular uses. The SAE-CD composition of the
invention has improved flow and dissolution performance as compared to
known compositions of SAE-CD.

Claims:

1-33. (canceled)

34. A sulfoalkyl ether cyclodextrin composition comprising: (a)
sulfoalkyl ether cyclodextrin; (b) no more than about 20% by weight
moisture; (c) a bulk density of about 0.38 g/cm3 to about 0.66
g/cm3; (d) a tapped density of about 0.49 g/cm3 to about 0.75
g/cm3, wherein the tapped density of the sulfoalkyl ether
cyclodextrin composition is higher than the bulk density; and (e) a
gravitational-flow minimum orifice diameter of about 3 mm to about 12 mm;
wherein the sulfoalkyl ether cyclodextrin composition comprises
agglomerated particles, and wherein the agglomerated particles are
produced by a process comprising: (i) forming a fluidized bed of
sulfoalkyl ether cyclodextrin particles in a drying chamber of a
fluidized bed spray dryer apparatus with an attached 3-chamber
fluidization bed; (ii) recycling fine particles from the fluidized bed
back into the drying chamber at a location adjacent to a liquid feed
atomizer; and (iii) collecting agglomerated particles from the third
chamber of the 3-chamber fluidization bed.

35. A sulfoalkyl ether cyclodextrin composition comprising: (a)
sulfoalkyl ether cyclodextrin; (b) no more than about 20% by weight
moisture; (c) a bulk density of about 0.55 g/cm3 to about 0.66
g/cm3; (d) a tapped density of about 0.66 g/cm3 to about 0.75
g/cm3, wherein the tapped density of the sulfoalkyl ether
cyclodextrin composition is higher than the bulk density; and (e) a
gravitational-flow minimum orifice diameter of about 3 mm to about 12 mm;
wherein the sulfoalkyl ether cyclodextrin composition comprises
agglomerated particles.

36. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin is a compound, or a mixture of compounds, of the Formula 1:
##STR00003## wherein: n is 4, 5, or 6; R1, R2, R3,
R4, R5, R6, R7, R8, and R9 are each,
independently, O.sup.- or a O--(C2-6 alkylene)-SO.sub.3.sup.- group,
wherein at least one of R1 and R2 is, independently, the
O--(C2-C6 alkylene)-SO.sub.3.sup.- group; and S1, S2,
S3, S4, S5, S6, S7, S8, and S9, are
each, independently, a pharmaceutically acceptable cation.

37. The composition of claim 34, wherein the sulfoalkyl ether
cyclodextrin composition comprises a bulk density of about 0.55
g/cm3 to about 0.66 g/cm3 and a tapped density of about 0.66
g/cm3 to about 0.75 g/cm.sup.3.

38. The composition of claim 34, wherein the sulfoalkyl ether
cyclodextrin composition comprises a bulk density of about 0.38
g/cm3 to about 0.55 g/cm3 and a tapped density of about 0.49
g/cm3 to about 0.66 g/cm.sup.3.

40. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin composition comprises a true density of about 1.1 g/cm3
to about 1.5 g/cm.sup.3.

41. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin composition comprises a CARR's index of about 12% to about
24%.

42. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin composition comprises particles with a mean particle
diameter of about 75 microns to about 200 microns.

43. The composition of claim 42, wherein at least 90% of the particle
volume of the sulfoalkyl ether cyclodextrin composition comprises
particles having calculated diameters greater than or equal to about 25
microns.

44. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin composition comprises a moisture content of about 2% to
about 3% by weight and a compression crushing strength of about 1.0 kP to
about 20 kP when compressed into a tablet using a Pmax of about 30 MPa to
about 275 MPa.

45. The composition of claim 35, wherein the sulfoalkyl ether
cyclodextrin composition comprises a moisture content of about 5% to
about 6% by weight and a compression crushing strength of about 0.5 to
about 11 kP when compressed into a tablet using a Pmax of about 15 MPa to
about 70 MPa.

46. The composition of claim 35, wherein 2.5 g of the sulfoalkyl ether
cyclodextrin composition has an average dissolution time of about 2 min
to about 4.5 min when placed in water.

47. A composition comprising the sulfoalkyl ether cyclodextrin
composition of claim 35 and an active agent.

48. The composition of claim 47, further comprising an excipient.

49. A composition comprising the sulfoalkyl ether cyclodextrin
composition of claim 35 and an excipient.

50. A pharmaceutical dosage form comprising a sulfoalkyl ether
cyclodextrin composition, wherein the sulfoalkyl ether cyclodextrin
composition comprises: (a) sulfoalkyl ether cyclodextrin; (b) no more
than about 20% by weight moisture; (c) a bulk density of about 0.38
g/cm3 to about 0.66 g/cm3; (d) a tapped density of about 0.49
g/cm3 to about 0.75 g/cm3, wherein the tapped density of the
sulfoalkyl ether cyclodextrin composition is higher than the bulk
density; and (e) a gravitational-flow minimum orifice diameter of about 3
mm, to about 12 mm; wherein the sulfoalkyl ether cyclodextrin composition
comprises agglomerated particles, and wherein the agglomerated particles
are produced by a process comprising: (i) forming a fluidized bed of
sulfoalkyl ether cyclodextrin particles in a drying chamber of a
fluidized bed spray dryer apparatus with an attached 3-chamber
fluidization bed; (ii) recycling fine particles from the fluidized bed
back into the drying chamber at a location adjacent to a liquid feed
atomizer; and (iii) collecting agglomerated particles from the third
chamber of the 3-chamber fluidization bed.

52. A pharmaceutical dosage form comprising a sulfoalkyl ether
cyclodextrin composition, wherein the sulfoalkyl ether cyclodextrin
composition comprises: (a) sulfoalkyl ether cyclodextrin; (b) no more
than about 20% by weight moisture; (c) a bulk density of about 0.55
g/cm3 to about 0.66/cm3; (d) a tapped density of about 0.66
g/cm3 to about 0.75 g/cm3, wherein the tapped density of the
sulfoalkyl ether cyclodextrin composition is higher than the bulk
density; and (e) a gravitational-flow minimum orifice diameter of about 3
mm to about 12 mm; wherein the sulfoalkyl ether cyclodextrin composition
comprises agglomerated particles.

56. The dosage form of claim 55, wherein the tablet is selected from the
group consisting of a controlled release tablet, an extended release
tablet, a compressed tablet, a compressed rapid release tablet, and an
orodispersable immediate release tablet.

57. The dosage form of claim 52, further comprising an excipient.

58. The dosage form of claim 52, further comprising an active agent.

59. A method of making a pharmaceutical dosage form, comprising:
combining a sulfoalkyl ether cyclodextrin composition and an active
agent, and processing the combination of the sulfoalkyl ether
cyclodextrin composition and the active agent to produce a dosage form,
wherein the sulfoalkyl ether cyclodextrin composition comprises: (a)
sulfoalkyl ether cyclodextrin; (b) no more than about 20% by weight
moisture; (c) a bulk density of about 0.55 g/cm3 to about 0.66
g/cm3; (d) a tapped density of about 0.66 g/cm3 to about 0.75
g/cm3, wherein the tapped density of the sulfoalkyl ether
cyclodextrin composition is higher than the bulk density; and (e) a
gravitational-flow minimum orifice diameter of about 3 mm to about 12 mm.

60. The method of claim 59, wherein the method further comprises
combining an excipient with the sulfoalkyl ether cyclodextrin composition
and the active agent.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.
12/108,228, filed Apr. 23, 2008, now U.S. Pat. No. 8,049,003, which is a
continuation of international Appl. No. PCT/US05/038933, filed Oct. 26,
2005, the entire disclosures of each of which are hereby incorporated by
reference.

FIELD OF THE INVENTION

[0002] The present invention relates to sulfoalkyl ether cyclodextrin
derivatives having improved physical properties and to methods of making
the same.

BACKGROUND OF THE INVENTION

[0003] The non-chemical physical property profile of a composition can
dramatically alter the in-process handling and performance, and possibly
the in vitro or in vivo performance, of a particular material. In other
words, a given chemical composition having a first physical property
profile might be suitable for inhalation; whereas, the same chemical
composition having a different second physical property profile might be
unsuitable for inhalation. Likewise, a particular excipient having a
first physical property profile might be better suitable for tabletting
by compression than would be the same excipient having a different second
physical property profile.

[0004] For example, the suitability of different physical forms of a
material used as a carrier for dry powder inhalation will vary according
to the non-chemical physical property profile of the various physical
forms of the material. The delivery of a drug by inhalation allows for
deposition of the drug in different sections of the respiratory tract,
e.g., throat, trachea, bronchi and alveoli. Generally, the smaller the
particle size, the longer the particle will remain suspended in air and
the farther down the respiratory tract the drug can be delivered. Drugs
are delivered by inhalation using a nebulizer, metered dose inhaler
(MDI), or dry powder inhaler (DPI).

[0005] Dry powder inhalers provide powder pharmaceuticals in aerosol form
to patients. In order to generate an aerosol, the powder in its static
state must be fluidized and entrained into the patient's inspiratory
airflow. The powder is subject to numerous cohesive and adhesive forces
that must be overcome if it is to be dispersed. Fluidization and
entrainment requires the input of energy to the static powder bed. The
particle size, shape, surface morphology and chemical composition of
carrier particles can influence aerosol dispersion. Increased drug
dispersion and deposition is generally observed with smaller carrier size
and increased proportion of fine particles. Elongated carriers generally
increased aerosol dispersibility and drug FPF (fine particle fraction),
possibly due to increased duration in the airstream drag forces. Carriers
with smooth surfaces produced higher respirable fractions. Low respirable
fractions were obtained from carriers with macroscopic surface roughness
or smooth surfaces, whereas high respirable fractions were obtained from
carriers with microscopic surface roughness, where smaller contact area
and reduced drug adhesion occurred at the tiny surface protrusions. Thus
for dry powder inhaler formulations, the size of carrier particles should
be selected on the basis of a balance between these interrelated
performance characteristics. Specifically, inter-particulate forces
should be such that the drug particles adhere to the carrier (to aid in
blending, uniformity, and allow the entrainment of drug into the
inspiratory air-stream), yet also allow detachment of the flue drug
particles from the surface of the coarser carrier particles so that
delivery to the lung can be facilitated. In view oldie above, different
physical forms oldie known solid carrier lactose may or may not be
suitable for dry powder inhalation.

[0006] The same general impact of physical form upon excipient behavior is
true for other pharmaceutical processes used to make dosage forms such as
a tablet, liquid, suspension, emulsion, film, laminate, pellet, powder,
bead, granule, suppository, ointment, cream, etc. In other words, a
single excipient will need to be made in different, physical forms in
order for it to be better suited for particular uses. For improved
tabletting by compression, for example, an excipient will preferably have
improved flow. Good flow characteristics are desirable in order to
facilitate handling and processing in a tablet press or capsule-filling
machine. It will also have a compressibility within a particular range
depending upon the role of the excipient in the tablet. If an excipient
is going to be used in a constitutable liquid formulation, the excipient
will preferably not clump when placed in the liquid and it will dissolve
completely and quickly. Even though many of these are highly desired
features in a solid excipient, it is very difficult to obtain any single
excipient having all of these features. For this reason, among others,
many different grades of excipients are developed in the pharmaceutical
industry.

[0007] Drying methods such as tray drying, freeze drying, spray drying,
fluidized bed spray granulation, and fluidized bed spray agglomeration,
among others, are used in the pharmaceutical industry to prepare solids
from feed solutions, emulsions, suspensions or slurries. The physical
properties of the isolated solid will depend upon the properties of the
feed material and the parameters employed in and the equipment used for
the drying method employed.

[0008] Spray drying entails atomizing a solids-containing feed solution or
suspension to form atomized droplets directed into a stream of hot gas in
a drying chamber thereby evaporating the liquid carrier from the droplets
resulting in the formation of spherical particles. Fluidized bed spray
drying is a modified form of spray drying wherein a spray dryings process
is performed in the presence of a fluidized bed (fluidized by the stream
of hot gas) of fine particles such that the atomized droplets collide
with and adhere to the fluidized particles. By modifying the solids
content of the feed solution and in the drying chamber, a spray drying
apparatus can be made to agglomerate or granulate the solids in a process
called fluidized bed spray agglomeration or fluidized bed spray
granulation, respectively. Moreover, the use of a rectangular versus
cylindrical spray drying apparatus will have an impact upon the physical
properties of the resulting product.

[0009] In an exemplary fluidized bed spray agglomeration/granulation with
a cylindrical apparatus, powder feed enters the solids feed inlet at a
controllable speed, and the liquid spray system sprays liquid feed from
the top or bottom of the fluidized bed into the material. Heated
fluidizing gas flows upward from the inlet through the bottom screen,
fluidizing the powder feed or seed particles in the fluidized-bed
chamber. Simultaneously, classifying gas flows upward through the
discharge pipe at a velocity that's controlled to blow fine particles
back into the fluidized bed, allowing only larger particles with a
falling velocity higher than the discharge pipe's classifying air
velocity to discharge through the pipe. This allows control of the
product's particle size while keeping the product dust-free. Dust removed
from the exhaust air by the circular unit's external dedusting equipment
can be recirculated to the recycle inlet for further processing. During
this process, the smaller particles fuse with each other or with lamer
particles to form agglomerates. As a result, the particle size
distribution of the particles in the fluidized bed increases such that
the percentage of fine particles present in the product is reduced as
compared to the fluidized feed material.

[0010] Solubilization of poorly water soluble compounds in aqueous media
is often very difficult. Therefore, artisans have employed solubilisation
enhancers, such as cyclodextrins, in the aqueous medium.
Parentunderivatized) cyclodextrins and their derivatives are well known
excipients that contain 6, 7, or 8 glucopyranose units and are referred
to as α-, β-, and γ-cyclodextrin, respectively. Each
cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3
positions and a primary hydroxyl group at the 6-position. The
cyclodextrins may be pictured as hollow truncated cones with hydrophilic
exterior surfaces and hydrophobic interior cavities.

[0011] β-CD has been reportedly prepared in a variety of different
forms using different finishing processes. American Maize Products
(French patent No. 2,597,485) recommends freeze-drying and spraying as
suitable methods for recovering cyclodextrin ethers from aqueous
solutions. However, the powders obtained according to these various
techniques have poor dissolution. In addition, these powders do not flow
easily and possess mediocre compression properties.

[0012] U.S. Pat. No. 6,555,139 to Sharma discloses a method for
microfluidizing β-CD in combination with a hydrophobic drug to yield
a smooth, latex-like microsuspension.

[0013] U.S. Pat. No. 5,674,854 to Bodley et al. discloses a composition
containing an inclusion complex of β-CD and diclofenac. The
composition can be prepared by spray agglomeration.

[0014] U.S. Patent Application Publication No. 20040234479 to
Schleifenbaum discloses a flavor or fragrance containing a cyclodextrin
particle containing the cyclodextrin particle and a flavor or fragrance,
wherein the cyclodextrin particle has a particle size in a range of 50 to
1000μ. The cyclodextrin particle comprises a cellulose ether and
cyclodextrin, wherein the cyclodextrin particle is obtained by a single
stage fluidized bed process from a spray mixture, and wherein a gas
introduction temperature is from 80° to 180° C. and a gas
outlet temperature is from 40° to 95° C.

[0015] European Patent Application No. EP 392 608 describes a method for
producing powdered cyclodextrin complexes wherein the particle size is
less than 12μ, preferably less than 5μ. Suitable processes for
doing so include spray-drying and freeze-drying. The '608 application
states that small particle sizes of CD often exhibit reduced pourability
or flowability and may dust easily. For this reason, the art suggests the
use of cyclodextrin complex particles having particle sizes of at least
50μ.

[0016] U.S. Patent Application Publication No. 20030065167 to Lis et al.
discloses a process for preparing a directly compressible β-CD. The
process includes "a step of dehydrating hydrated beta-cyclodextrin to a
water content of less than 6%, preferably less than 4% and more
preferably still less than or equal to 2% by weight, followed by forced
rehydration to a water content greater than 10%, preferably greater than
12% and more preferably still greater than or equal to 13% by weight.

[0017] The impact of the drying step or finishing step in the preparation
of hydroxypropyl-β-cyclodextrin (HP-β-CD) obtained from a syrup
containing the same has been explored. U.S. Patent Application
Publication No. 20030028014 to Sikorski et. al. discloses an agglomerated
HP-β-CD and a process from making the same. The agglomerated product
is made in a double drum dryer. It reportedly has low dusting and good
dissolution in water. The particle size of the product is about 30 to
200μ.

[0018] U.S. Pat. No. 5,756,484 to Fuertes et al. discloses a pulverulent
HP-β-CD composition and a method for its preparation. The
HP-β-CD has a centered particle size free or fine particles and an
appreciably improved capacity to dissolve in aqueous medium. The
HP-β-CD is made by spraying a solution of HP-β-CD on a moving
pulverulent bed of HP-β-CD particles.

[0019] The physical and chemical properties of the parent cyclodextrins
can be modified by derivatizing the hydroxyl groups with other functional
groups. One such derivative is a sulfoalkyl ether cyclodextrin.

##STR00001##

[0020] Sulfoalkyl ether cyclodextrin (SAE-CD) derivatives are well known
as are their uses in a wide range of applications. SAE-CD derivatives are
particularly useful in solubilizing and/or stabilizing drugs. A
sulfobutyl ether derivative of beta cyclodextrin (SBE-β-CD), in
particular the derivative with an average of about 7 substituents per
cyclodextrin molecule (SBE7-β-CD), has been commercialized by CyDex,
Inc. as CAPTISOL®. The anionic sulfobutyl ether substituent
dramatically improves the aqueous solubility of the parent cyclodextrin.
In addition, the presence of the charges decreases the ability or the
molecule to complex with cholesterol as compared to the hydroxypropyl
derivative. Reversible, non-covalent, complexation of drugs with
CAPTISOL® cyclodextrin generally allows for increased solubility and
stability of drugs in aqueous solutions.

[0021] CAPTISOL®, prepared by spray drying, is used in the commercial
formulations VFEND® and GEODON®. It has become a leading
cyclodextrin derivative for use in pharmaceutical formulations and thus
is important to the industry.

[0022] Methods of preparing SAE-CD derivatives are varied but generally
include the general steps of sulfoalkylation followed by isolation. The
chemical property profile of the SAE-CD is established during the
sulfoalkylation step. For example, altering reaction conditions during
sulfoalkylation can vary the average degree of substitution for and the
average regiochemical distribution of sulfoalkyl groups in the SAE-CD.
The alkyl chain length of the sulfoalkyl functional group is determined
according the sulfoalkylating agent used. And use of a particular
alkalizing agent during alkylation would result in formation of a
particular SAE-CD salt, unless an ion exchange step were performed
subsequent to sulfoalkylation.

[0023] In general, known processes for the sulfoalkylation step include,
for example: 1) exposure of underivatized parent cyclodextrin under
alkaline conditions to an alkylating agent, e.g. alkyl sultone or a
haloalkylsulfonate; 2) optional addition of further alkalizing agent to
the reaction milieu to consume excess alkylating agent; and 3)
neutralization of the reaction medium with acidifying agent. The vast
majority of literature processes conduct the sulfoalkylation step in
aqueous media; however, some references disclose the use of pyridine,
dioxane, or DMSO as the reaction solvent for sulfoalkylation. Literature
discloses the use of an alkalizing agent in order to accelerate the
sulfoalkylation reaction. Upon completion of the sulfoalkylation step,
isolation and purification of the SAE-CD is conducted.

[0025] The art, therefore, is lacking teaching on the methods of preparing
and using SAE-CD derivatives having particular non-chemical physical
property profiles. Given the importance of SAE-CD to the pharmaceutical
industry, it would be a significant improvement in the art to provide
SAE-CD derivatives having particular non-chemical physical property
profiles so that such forms can be tailored for particular purposes.

SUMMARY OF THE INVENTION

[0026] The present invention seeks to overcome the disadvantages present
in known dry powder compositions of SAE-CD. As such, a derivatized
cyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin (SAE-CD)-based,
composition is provided. The present SAE-CD composition excludes a
principal active agent. However, the composition possesses unexpectedly
advantageous physical properties that exist as a result of the method
used to remove water from an aqueous medium containing SAE-CD. The
composition prepared by the process of the invention provides solid
SAE-CD in particulate form.

[0027] The physical properties of the SAE-CD are modulated through a
variety of techniques to yield different grades of SAE-CD (a SAE-CD grade
or SAE-CD composition) wherein each is adapted for use in specific dosage
forms, such as a tablet, capsule, constitutable powder, dry powder
inhaler, sache, troche, and lozenge. The properties can also be modified
for improved handling, packaging, storage and other process related
activities. Also, the chemical properties can be adapted for particular
uses by changing the identity of the counterion, changing the alkyl chain
length, average degree of substitution, or ring size of the parent
cyclodextrin from which the SAE-CD is made. The properties can also be
adapted for particular uses by changing the non-chemical physical
properties of the SAE-CD such as by changing the mean or average particle
diameter, the span of the particles size distribution, the water content
of the SAE-CD, the surface characteristics of the SAE-CD particles, the
rate of dissolution of the particles, the bulk density, the tap density,
the Carr Index, compressibility, flowability and more.

[0028] The SAE-CD compositions of the invention possess numerous
advantages over known compositions of SAE-CD, i.e., those prepared
according to known methods that differ in the post-sulfoalkylation steps.
The SAE-CD compositions herein provide an unexpectedly improved aqueous
dissolution rate, compression crushing strength, ease of tabletting,
and/or improved solids handling.

[0029] One form of a SAE-CD composition is provided containing no more
than about 20% by wt. moisture. The SAE-CD composition can be included in
a dry formulation in admixture with an active agent such that all or
substantially all of the active agent is not complexed with the SAE-CD.
The SAE-CD composition can be included in a dry formulation in admixture
with one or more excipients. The SAE-CD composition can also be included
in a constitutable formulation.

[0030] The particulate SAE-CD compositions of the invention possess
morphological and physicochemical properties that predispose them to
dissolve more rapidly than previously known compositions of SAE-CD such
as those prepared by spray drying. The SAE-CD compositions, prepared by
the processes described herein, possess particular combinations of
morphological and physicochemical properties. In some embodiments, the
process is fluidized bed spray agglomeration. In some embodiments, the
particulate SAE-CD composition is prepared by fluidized bed spray
granulation, and the resulting. SAE-CD composition possesses a different
combination of physical properties than does a SAE-CD composition
prepared by fluidized bed spray agglomeration.

[0031] When SAE-CD particles are prepared by known methods, they do not
possess the advantageous combination of physical properties as that found
in the SAE-CD composition of the invention. A SAE-CD composition
disclosed herein is prepared by a process comprising:

[0032] providing an aqueous liquid feed comprising water and SAE-CD; and

[0033] subjecting the liquid feed to a combination fluidized bed spray
drying process whereby the SAE-CD is agglomerated (and/or granulated) and
dried to below the point of deliquescence to form a particulate SAE-CD
composition comprising agglomerated (and/or granulated) particles wherein
at least 90% of the particle volume of the SAE-CD composition is made of
particles having calculated diameters greater than or equal to about 25
microns. (The particle diameter cut-off for the 10% cumulative volume
fraction is 25 microns or greater.) The SAE-CD composition can possess a
tapped density in the range of about 0.66 to 0.75 g/cm3 or about
0.49 to 0.75 g/cm3 when determined according to USP <616>
Method 1 and/or a bulk density in the range of about 0.55 to 0.66
g/cm3 or about 0.38 to about 0.66 g/cm3 when determined
according to USP <616> Method 1. For a specific SAE-CD composition,
the tapped density is higher than the bulk density.

[0034] The moisture content of the SAE-CD composition is below its point
of deliquescence. However, particular embodiments include those having a
moisture content of ≦18% by wt., ≦16% by wt., ≦15%
by wt., ≦10% by wt., or ≦5% by wt.

[0035] The SAE-CD composition is particulate and has a mean particle
diameter of about 92 to about 200 microns, or less than or equal to about
110 microns, or less than or equal to about 200 microns. The mean
particle diameter has been determined according to Example 3 with a
Malvern instrument. This instrument measures particle diameter via low
angle laser light scattering and calculates particle diameter based upon
the volume of an assumed spherical shape. The term "mean particle
diameter" is defined as the volume moment mean, otherwise known as the De
Brouckere mean diameter, D[4,3]. The SAECD composition can be prepared by
fluidized bed spray agglomeration or fluidized bed spray granulation.

[0036] The SAE-CD composition has a combination of physical properties
that render it better suited than previously known SAE-CD compositions
for use in compressed tablet formulations. For example, the SAE-CD
composition has a compression crushing strength in the range of about 1.0
to about 20 kP when 200 mg of SAE-CD composition are compressed into a
tablet having a diameter of 0.345 inches using a Pmax (peak compression
pressure) in the range of about 30 to about 275 MPa and the SAE-CD
composition has a moisture content in the range of about 2 to about 3% by
wt. as determined by LOD. Alternatively, the SAE-CD composition has a
compression crushing strength in the range of about 0.5 to 11 KP when 200
mg of SAE-CD composition are compressed into a tablet having a diameter
of 0.345 inches using a Pmax MPa in the range of about 15-70 MPa and the
SAE-CD has a moisture content in the range of about 5-6% by wt.

[0037] The SAE-CD composition possesses a more rapid dissolution rate in
water than does SAE-CD prepared by conventional spray drying. When 2.5 g
of SAE-CD composition is assayed according to Example 6, it has an
average dissolution time of 2.5 minutes or less, or 4.5 minutes or less,
or 3.5 minutes or less when placed in water.

[0038] A SAE-CD composition having an advantageous flow property is
provided by the invention. For example, the SAE-CD composition has a
gravitational-flow minimum orifice diameter of about 3-7 mm or 4-6 mm, or
less than about 10 mm or less than about 20 mm. The method of Example 5
can be followed to determine the gravitational-flow minimum orifice
diameter.

[0039] Density of the SAE-CD composition can be controlled. The SAE-CD
composition has a true density of 1.25 to 1.35 g/cm3 or 1.1 to 1.5
g/cm3. Embodiments of the SAE-CD composition include those having a
bulk density of about 0.55 to about 0.66 g/cm3, about 0.38 to less
than about 0.55 g/cm3, or about 0.38 to about 0.66 g/cm3 when
performed according to USP <616> Method 1. Other embodiments have a
tap density (tapped density) of about 0.66 to about 0.75 g/cm3, or
about (1.49 to about 0.66 g/cm3 or about (1.49 to about 0.75
g/cm3 when performed according to USP <616> Method 1.
Additionally or alternatively, the SAE-CD composition has a CARR's index
of less than or about 24% or less than or about 18% or less than or about
16%.

[0040] Another aspect of the invention provides a SAE-CD composition
having a moisture content below its point of deliquescence, a bulk
density in the range of about 0.55 to 0.66 g/cm3, and a tapped
density in the range of about 0.66 to 0.75 g/cm3, a CARR's index of
less than or about 24%; and optionally, a moisture content of less than
about 18% by wt., optionally a true density in the range of about 1.1 to
1.5 g/cm3, optionally a gravitational-flow minimum orifice diameter
of less than about 20 mm, optionally, wherein the SAE-CD composition is
prepared by fluidized bed spray agglomeration or fluidized bed spray
granulation.

[0042] The SAE-CD composition can be included in a formulation (e.g.
solid, liquid, gel, suspension, emulsion, or other known formulation)
comprising one or more active agents and, optionally, one or more
excipients. Therefor, the invention also provides a method of treating
diseases or disorders by administration to a subject of the SAE-CD
composition in a formulation further comprising an active agent.

[0043] In one embodiment, the properties of the SAE-CD composition can be
modulated such that different physicochemical properties are matched to
drug particle properties for optimizing dispersion from dry powder
inhalers.

[0045] Another aspect of the invention provides an improved solid
formulation, the improvement comprising including in the formulation a
SAE-CD composition of the invention, wherein the SAE-CD has been prepared
by a fluidized bed spray drying process (agglomeration or granulation) or
a SAE-CD composition possessing a physical property profile as defined
herein. These and other aspects of this invention will be apparent upon
reference to the following detailed description, examples, claims and
attached figures.

BRIEF DESCRIPTION OF THE FIGURES

[0046] The following drawings are given by way of illustration only, and
thus are not intended to limit the scope of the present invention.

[0047] FIG. 1 depicts a SEM (scanning electron microscope) photograph of
an exemplary batch of SAE-CD composition made according to the invention.
The SAE-CD particles were made according to different
post-sulfoalkylation processes.

[0050] FIG. 4 is a graph depicting the relationship between crushing
strength and compression pressure for SAE-CD compositions of the
invention containing differing amounts of moisture.

DETAILED DESCRIPTION OF THE INVENTION

[0051] The compositions of SATE-CD are adapted for use in particular
applications. When used in those applications, the present compositions
of SAE-CD are advantageous over and provide improved performance over
previously known compositions of SAE-CD for those applications. By
varying the finishing conditions (post-sulfoalkylation steps, steps
occurring subsequent to the sulfoalkylation step), one is able to modify
the physicochemical and morphological properties of the SAE-CD. For
example, different SAE-CD compositions can be obtained by varying the
drying and isolation conditions.

[0052] Even though the SAE-CD composition of the invention does not
require attritting, it can be attritted to provide even further modified
SAE-CD compositions. For example, attritting an SAE-CD composition
prepared by fluidized bed spray drying can result in an SAE-CD
composition having a different bulk density, tapped density, and/or
particle diameter. As used herein, the term attritting means to
physically abrade a solid to reduce its particle size. Any such process
used in the pharmaceutical industry is suitable for use in the process of
the invention. Attrition processes include, by way of example and without
limitation, micronizing, ball milling, jet milling, hammer milling, pin
milling, tumbling, sieving, and mortar and pestle. Both low and high
energy methods can be used.

[0053] The present invention provides a "SAE-CD composition", meaning a
composition of sulfoalkyl ether cyclodextrin having a combination of
different physical properties and excluding an active agent or
pharmaceutical excipient. As regards the SAE-CD composition, the term
"excluding" means not purposefully added. Therefore, it is possible for
the SAE-CD composition to contain excipients endogenous to its method of
manufacture. For example, a first SAE-CD composition will have a first
combination of physical properties, i.e. a first physical property
profile, and the second SAE-CD composition will have a second combination
of physical properties. By virtue of the different combinations of
physical properties, the first SAE-CD composition will be more
advantageous for a particular use, and the second SAE-CD composition will
be more advantageous for another particular use.

[0054] The present invention provides SAE-CD compositions, wherein the
SAE-CD is a compound of the Formula 1, or a combination thereof:

[0060] The SAE-CD raw material is included in the liquid feed used in the
fluidized bed spray drying process employed to prepare an SAE-CD
composition of the invention.

[0061] The SAE-CD composition of the invention can also include a
combination of derivatized cyclodextrin (SAE-CD) and underivatized
cyclodextrin. For example, a SAE-CD composition can be made to include
underivatized cyclodextrin in the amount of 0 to less than 50% by wt. of
the total cyclodextrin present. Exemplary embodiments of the SAE-CD
composition include those comprising 0-5% by wt., 5-50% by wt., less than
5%, less than 10%, less than 20%, less than 30%, less than 40%, or less
than 50% underivatized cyclodextrin.

[0062] The terms "alkylene" and "alkyl," as used herein (e.g., in the
O--(C2-C6 alkylene)-SO3.sup.- group or in the
alkylamines), include linear, cyclic, or branched, and saturated or
unsaturated (i.e., containing one double bond) divalent alkylene groups
or monovalent alkyl groups, respectively. The term "alkanol" in this text
likewise includes both linear, cyclic and branched, saturated and
unsaturated alkyl components of the alkanol groups, in which the hydroxyl
groups may be situated at any position on the alkyl moiety. The term
"cycloalkanol" includes unsubstituted or substituted (e.g., by methyl or
ethyl) cyclic alcohols.

[0063] Some embodiments of the present invention provide compositions
containing a single type of cyclodextrin derivative having the structure
set out in formula (I), where the composition overall contains on the
average at least 1 and up to 3n+6 alkylsulfonic acid moieties per
cyclodextrin molecule. The invention also includes compositions
containing cyclodextrin derivatives having a narrow or wide range for
degree of substitution and high or low degree of substitution. These
combinations can be optimized as needed to provide cyclodextrins having
particular properties.

[0064] Exemplary SAE-CD derivatives include SBE4-β-CD,
SBE7-β-CD, SBE11-β-CD, SBE7-γ-CD and SBE5-γ-CD
which correspond to SAE-CD derivatives of the formula 1 wherein n=5, 5,
5, 6 and 6, respectively; m is 4; and there are on average 4, 7, 11, 7
and sulfoalkyl ether substituents present, respectively. Other exemplary
SAE-CD derivatives include those of the formula SAEx-R-CD (Formula 2),
wherein SAE is sulfomethyl ether (SME), sulfoethyl ether (SEE),
sulfopropyl ether (SPE), sulfobutyl ether (SBE), sulfopentyl ether
(SPtE), or sulfohexyl ether (SHE); x (average or specific degree of
substitution) is 1-18, 1-21, 1-24, when R (ring structure of parent
cyclodextrin) is α, β or γ, respectively; and CD is
cyclodextrin. The SAE functional group includes a cationic counterion as
disclosed herein or generally as used in the pharmaceutical industry for
the counterion of any acidic group.

[0065] Since SAE-CD is a poly-anionic cyclodextrin, it can be provided in
different salt forms. Suitable counterions for the SAE functional
group(s) include cationic organic atoms or molecules and cationic
inorganic atoms or molecules. The SAE-CD can include a single type of
counterion or a mixture of different counterions. The properties of the
SAE-CD can be modified by changing the identity of the counterion
present. For example, a first salt form of SAE-CD can have a greater
electrostatic charge than a different second salt form of SAE-CD. The
calcium salt form has been found to be more electronegative than the
sodium salt form. Likewise, a SAE-CD having a first degree of
substitution can have a greater electrostatic charge than a second SAE-CD
having a different degree of substitution.

[0066] When the SAE-CD composition is intended for intra-pulmonary
administration, the median particle diameter can be in the range of about
0.1 to about 10 microns or about 0.5 to about 6.4 microns. If it is
desired that the particles reach the lower regions of the respiratory
tract, i.e., the alveoli and terminal bronchi, the median particle
diameter size range can be in the range of about 0.5 to about 2.5
microns. If it is desired that the particles reach the upper respiratory
tract, the particle diameter size range can be between 2.5 microns and 10
microns. A SAE-CD composition with this median particle diameter size can
be prepared by attritting a SAE-CD composition having a larger median
particle diameter size range.

[0067] The particle diameter span (defined as the ratio=(mean particle
diameter of the 90th percentile-mean particle diameter of 10th
percentile)/mean particle diameter of the 50th percentile) of the
SAE-CD composition can also impact its performance. SAE-CD having broad,
moderate and narrow particle size distribution may be used in the
invention. A larger span indicates a broader particle size distribution
and a smaller span indicates a narrower particle size distribution.
Specific embodiments include those wherein the span is in the range of
about 1.5 to 2.9, 1.1 to 1.9, or 1.4 to 1.7.

[0068] Since particles are present as a distribution of sizes, the
distribution can be monomodal, bimodal or polymodal, the preferred being
monomodal distribution.

[0069] The SAE-CD composition is a particulate composition containing
agglomerated and non-agglomerated particles. Agglomerated particles can
be prepared by fluidized bed spray drying, which can include
agglomeration and/or granulation. The term agglomeration, which can be
used interchangeably with granulation, is taken to mean a process in
which dispersed fine particles in a composition are fused with other
particles in the composition to form a coarser particulate composition
thereby reducing the amount of fine particles and increasing the overall
mean particle diameter of the composition. The collection of particles
that results can be called an agglomerate or granulate. The SAE-CD
composition of the invention is distinguishable by SEM from other
compositions of SAE-CD made according to other processes. FIG. 1 depicts
a SEM of an exemplary SAE-CD composition made by fluidized bed spray
drying. The particles have a rough surface texture and comprise a
substantial amount of agglomerated particles.

[0070] Exemplary processes for the preparation of the SAE-CD composition
include fluidized bed spray agglomeration or fluidized bed spray
granulation.

[0071] FIG. 2 depicts an exemplary fluidized bed spray dryer system that
can be used to prepare a SAE-CD composition of the invention. This system
includes a liquid feed tank (1), cylindrical fluidized bed spray drying
unit (2), cyclone particle classifier (3), finished-product collection
container (4), gas filtration unit (5), waste-product collection
container (6), condensers (7), and fluidized bed chambers (8-10). The
system can be operated as follows. To begin the process, an aqueous
liquid feed containing SAE-CD raw material is transferred from the tank
(1) to the dryer (2) via conduit (M). The liquid feed is atomized into
the drying chamber in a counter-current manner against the hot gas stream
(A) to form an initial fluidized bed of particles. The fine particles
formed exit the drying chamber and are conducted via conduit (B) to the
cyclone (3), which classifies the particles and returns
appropriately-sized line particles via conduit (C) back into the upper
portion of the drying chamber at a location adjacent to and in a
co-current fashion with the liquid feed. As additional liquid feed is
atomized into the drying chamber larger particles and fine particles are
formed, and the larger particles (those not considered "fine" particles)
form the fluidized bed in chamber (8). When the particles reach the
intended mean particle diameter size, they are conducted to chamber (9),
and subsequently, chamber (10). Each chamber includes its own gas inlet
and contains a fluidized bed of particles. The gas inlet for chamber (8)
is the main hot gas stream (A) that fluidizes the bed of particles in the
drying chamber (8). The gas stream (N) for chamber (9) is lower in
temperature than the stream (A), and the stream (P) is even lower in
temperature. As the panicles move from chamber (8) to chamber (9) and
then chamber (10), they are cooled. The finished SAECD composition is
collected from chamber (10) and conducted to the container (4) via a
conduit (F). Fine particles present in chambers (9) and (10) are
conducted via conduit (G) to the cyclone (3). Gas exiting the cyclone is
conducted via conduit (H) into the filter unit (5) to collect any
particles not otherwise recycled by the cyclone to the drying chamber.
Particles collected in the filter unit are loaded into a collection
container (6) for possible reprocessing. Gas exits the filter unit and is
conducted through the condenser(s) (7), which remove moisture from the
gas. Finally, the gas is either vented or returned back to the drying
chamber via conduit (L) and/or the gas streams (A, N, or P).

[0072] FIG. 3 depicts another exemplary fluidized bed spray dryer system
that can be used to prepare a SAE-CD composition of the invention. This
system is similar to that of FIG. 2; however, it excludes the chambers
(9-10), the particle-recycle conduit (G), and the condenser(s) (7).
Moreover, the cyclone returns the fine particles to the drying chamber
via conduit (C) and subsequently conduit (C1) and/or conduit (C2). When
the fines are introduced into the drying chamber via the conduit (C1),
they are introduced in a co-current manner with the flow of liquid feed
being atomized into the drying chamber. When the fines are introduced
into the drying chamber via the conduit (C2), the fines are introduced in
a direction that is tangential to or perpendicular to the flow of gas
stream (A) being introduced into the drying chamber and/or the gas inlet
(L). Note that this exemplary system does not return gas from the
filtration unit back into the drying chamber; however, it can be modified
to do so.

[0073] Most particles in such fluidized bed chambers typically do not
reach the height of the cloud of atomized liquid feed. However, fine
panicles formed during the process that are recycled back into the drying
chamber can be introduced at a location adjacent the liquid feed atomizer
or at a location between the atomizer and the fluidized bed.

[0074] During operation of either system, the flow of gas stream can be
adjusted at various locations within the system in order to modify bed
fluidization, drying rate, fines classification, and/or feed rate of the
fines into the drying chamber. Fluidized bed spray drying process
includes:

[0076] providing in a drying chamber a fluidized bed of SAE-CD particles
having a first mean particle diameter size, wherein the bed is fluidized
with a stream of hot gas flowing in a first direction;

[0077] atomizing the liquid feed onto the fluidized bed in the drying
chamber to form a particulate SAE-CD composition comprising agglomerated
particles having a greater second mean particle diameter size, wherein
the atomization is conducted in a second direction and a majority of the
liquid carrier has been removed from the particulate composition; and

[0078] collecting the particulate composition to form the SAE-CD
composition.

[0079] Specific embodiments of the processes include those wherein: 1) the
process further comprises recycling a portion of the smaller particles in
the particulate composition back to the drying chamber; 2) the recycled
portion of particles is introduced into the drying chamber at a location
adjacent the point of introduction of the liquid feed; 3) the recycled
portion of particles is introduced into the drying chamber in a direction
tangential or perpendicular to the direction of introduction of the
liquid feed into the drying chamber; 4) the recycled portion of particles
is introduced into the drying chamber at a location adjacent the cone of
the drying chamber; 5) the process is conducted in a co-current manner;
6) the process is conducted in a counter-current manner; 7) the process
is conducted in a mixed flow manner; 8) the particulate composition
comprises less than 18% by wt. of liquid carrier; 9) the liquid carrier
is aqueous; 10) the liquid feed comprises SAE-CD; 11) the SAE-CD
composition possesses a combination of physical properties as described
herein; and 12) the fluidized bed spray dryer has a cylindrical and/or
conical drying chamber.

[0080] In a co-current fluidized bed spray drying process, the direction
of flow of the atomized liquid feed in the drying chamber is the same as
the direction of flow of the hot air used to fluidize the bed of
particles. The atomizer can be a spray nozzle or a rotary atomizer (e.g.
rotating disk). The air current can be controlled such that laminar or
turbulent flow occurs predominantly.

[0081] In a counter-current fluidized bed spray drying process, the hot
air used to fluidize the bed moves through the drying chamber in a
direction opposite that of the atomized liquid feed.

[0082] In a mixed flow fluidized bed spray drying process, particles move
through the drying chamber in both co-current and counter-current phases.
This mode requires the use of a nozzle atomizer spraying upwards into an
incoming airflow or an atomizer spraying droplets downwards towards an
integrated fluid bed, wherein the air inlet and outlet are located at the
top of the drying chamber. Additional air inlets will direct flow upwards
to fluidize the bed of particles.

[0083] The line or small particles used to form the fluidized bed in the
drying chamber can be prepared separately such as by spray drying,
milling, grinding, otherwise attritting, sieving, or other suitable
means. Otherwise, the fine particles can be prepared in situ by operating
the equipment as a conventional spray dryer and subsequently operating
the equipment as a fluidized bed spray dryer. In one embodiment, the line
or small particles are obtained by separating those particles from the
material removed from the drying chamber and recycling the fine or small
particles back into the drying chamber. The invention includes processes
whereby the fine particles are introduced into the drying chamber and/or
are generated in situ by virtue of drying of the atomized liquid feed.

[0084] The process of the invention can be run in a continuous or
semicontinuous manner whereby liquid feed containing SAE-CD raw material
is introduced into the drying chamber continuously or semicontinuously
and SAE-CD composition is removed from the fluidized bed continuously or
semicontinuously.

[0085] The aqueous liquid carrier used in the liquid feed, which can be a
solution or slurry, may or may not contain another material, such as
by-product(s) of the sulfoalkylation reaction and subsequent basification
oldie reaction milieu. As used herein, a liquid carrier is any aqueous
medium used in the pharmaceutical sciences used to agglomerate or
granulate solids.

[0086] The SAE-CD solids content of the liquid feed can range from 0.1 to
80% by wt., 10 to 70% by wt., 30 to 70% by wt., or 40 to 60% by wt.
solids. Some embodiments of the liquid feed comprise: 1) only sulfoalkyl
ether cyclodextrin and water; or 2) only sulfoalkyl ether cyclodextrin,
water and by-products of the synthetic process used to prepare the
sulfoalkyl ether cyclodextrin. The sulfoalkyl ether cyclodextrin used in
the liquid feed is sometimes referred to herein as the sulfoalkyl ether
cyclodextrin raw material.

[0087] The liquid feed can be cooled or heated prior to entry into the
drying chamber. Temperature can be used to control viscosity of the
liquid feed: the higher the temperature, the lower the viscosity. The
temperature of the liquid feed can be 0° C. to 100° C., or
ambient temperature to 70° C.

[0088] The gas used to conduct particles throughout the system is
generally a gas such as air, helium, or nitrogen. The system can include
a gas-charging unit to load gas for operation, purging and
supplementation.

[0089] The temperature of the inlet gas can be used to control drying rate
of the particles, production rate, extent of agglomeration, water content
of the SAE-CD composition and/or type of agglomeration. The temperature
can vary from about 100° to about 300° C., about
130° to about 180° C., about 150° to about
170° C., or about 210° to about 250° C.

[0090] The SAE-CD composition has a gravitational-flow minimum orifice
diameter ranging from about 3-7 mm or 4-6 mm, or less than about 10 mm or
less than about 20 mm. The term "gravitational-flow minimum orifice
diameter" means the minimum diameter of an orifice through which the
SAE-CD composition will provide an acceptable bulk flow. The example
below further defines the term. This parameter is determined according to
the method of Example 5 wherein a FLOWDEX (Hanson Research Corp.
Northridge, Calif.) apparatus is used. The present inventors have
succeeded in preparing a SAE-CD composition that has a substantially
different minimum orifice diameter than has been prepared by conventional
spray drying.

[0091] The SAE-CD composition has a CARR's index of less than or about 24%
compressibility or less than or about 18% compressibility or less than or
about 16% compressibility. As used in this regards, "compressibility"
refers to the relative percent reduction that a particulate mass will
undergo during the tapped density determination. The CARR's index is a
measure of the compressibility of a SAE-CD composition. It is based upon
the bulk and tapped density of the material. The CARR's index has been
determined according to Example 8 below. The present inventors have
succeeded in preparing a spray agglomerated SAE-CD composition having a
CARR's index substantially different to other SAE-CD compositions
prepared by spray drying, freeze-drying, or spray agglomeration.

[0092] The SAE-CD has a true density in the range of about 1.25 to 1.35
g/cm3 or 1.1 to 1.5 g/cm3 or 1.29 to 1.32 g/cm3. True
density has been determined according to Example 8 below. The SAE-CD
composition of the invention has a substantially different true density
than a SAE-CD composition prepared by spray drying.

[0093] The SAE-CD composition has a bulk density of about 0.55 to 0.66
g/cm3 about 0.38 to less than 0.55 g/cm3, or about (1.38 to
about 0.66 g/cm3. The SAE-CD composition made according to the spray
agglomeration process of the invention has a higher bulk density than
that of a SAE-CD composition made by another spray dry agglomeration
process.

[0094] The SAE-CD composition has a tapped density (tap density) of about
0.66 to 0.75 g/cm3, or about 0.49 to 0.66 g/cm3 or about 0.49
to about 0.75 g/cm3 when performed according to USP <616>
Method 1. The SAE-CD composition made according to the spray
agglomeration process of the invention has a higher tap density than that
of a SAECD composition made by another spray dry agglomeration process.

[0095] Since solid SAE-CD composition can be used for the manufacture of
tablets, especially compressed tablets, its compression crushing strength
at different peak compression pressures was determined with SAE-CD
compositions having different moisture contents. The method of Example 7
was used to determine this relationship. SAE-CD composition performance
was compared (FIG. 4) to that of Avicel PH-200, lactose and Dical, which
are three excipients commonly used in the manufacture of tablet
formulations. The SAE-CD composition of the invention is highly
advantageous, as its compression behavior can be improved by changing its
moisture content, particle size and/or particle shape.

[0096] Tablet Hardness or Tablet Crushing Strength in units of kiloponds
(kP) versus Peak Compression Pressure (Pmax) in units of megapascals
(MPa) is presented for SAECD composition (SBE7-β-CD) sample
(B3, B4) of this invention used `as is`, i.e. as obtained from the
fluidized bed spray drying process, and equilibrated (B3 Eq and B4 Eq)
over saturated magnesium nitrate. The performance of those samples was
compared to that of commercial direct compression bulk excipients, e.g.
microcrystalline cellulose or MCC (Avicel PH 200, FMC), lactose
monohydrate (SuperTab, The Lactose Co. of New Zealand), dibasic calcium
phosphate dihydrate (Emcompress, Penwest Pharm Co.). For the tooling used
in this study, 100 MPa is approximately equivalent to 6 kN of force. The
`as is` water content of the SAE-CD composition of this invention was
2.77% and 2.36% for B3 and B4, respectively, as determined by Loss on
Drying (LOD) at 110 C via Computrac Model 2000XL (Arizona Instruments,
Tempe, Ariz.). The water content after equilibration as determined by LOD
was 5.46% and 5.50% for 83 Eq and B4 Eq, respectively.

[0097] At lower levels of moisture content, e.g. in the range of about 2
to about 3% by wt. (as determined by LOD run at 104° to
110° C.), the SAE-CD composition had a compression crushing
strength in the range of about 1 to about 20 kP (kiloponds) when
compressed into a tablet using a Pmax (peak compression pressure) in the
range of about 30 to about 275 MPa (megapascals). At higher levels of
moisture content, e.g. in the range of about 5 to about 6% by wt. (as
determined by LOD), the SAE-CD composition had a compression crushing
strength in the range of about 0.5 to about 11 kP when compressed into a
tablet using a Pmax in the range of about 15 to about 70 MPa. The mean
particle diameter, particle diameter size distribution, and morphology of
the SAECD composition are readily modified to match the wide variety of
micronized drug characteristics that are presented to a formulator of the
art. An advantage of the present invention is the ability of an artisan
to modulate the physicochemical properties of the SAE-CD composition to
match or complement formulation or manufacturing processes, drug
properties or excipient properties thereby resulting in an optimal
product.

[0101] The active agents (drugs) listed herein should not be considered
exhaustive and is merely exemplary of the many embodiments considered
within the scope of the invention. Many other active agents can be
administered with the composition of the present invention. Suitable
drugs are selected from the list of drugs included herein as well as from
any other drugs accepted by the U.S.F.D.A. or other similarly recognized
authority in Canada (Health Canada), Mexico (Mexico Department of
Health), Europe (European Medicines Agency (EMEA)), South America (in
particular in Argentina (Administracion Nacional de Medicamentos,
Alimentos y Tecnolouia Medica (ANMAT) and Brazil (Ministerio da Sa de)),
Australia (Department of Health and Ageing), Africa (in particular in
South Africa (Department of Health) and Zimbawe (Ministry of Health and
Child Welfare),) or Asia (in particular Japan (Ministry of Health, Labour
and Welfare), Taiwan (Executive Yuans Department of Health), and China
(Ministry of Health People's Republic of China)) as being suitable for
administration to humans or animals. Some embodiments of the invention
include those wherein the active substance is pharmacologically or
biologically active or wherein the environment of use is the GI tract of
a mammal.

[0102] The active agent can be present in its neutral, ionic, salt, basic,
acidic, natural, synthetic, diastereomeric, epimeric, isomeric,
enantiomerically pure, racemic, solvate, hydrate, anhydrous, chelate,
derivative, analog, esterified, non-esterified, or other common form.
Whenever an active agent is named herein, all such forms available are
included.

[0103] An active agent contained within the present formulation can be
present as its pharmaceutically acceptable salt or salt-free form. As
used herein, "pharmaceutically acceptable salt" refers to derivatives of
the disclosed compounds wherein the active agent is modified by reacting
it with an acid or base as needed to form an ionically bound pair.
Examples of pharmaceutically acceptable salts include conventional
non-toxic salts or the quaternary ammonium salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. Suitable
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,
nitric and others known to those of ordinary skill in the art. The salts
prepared from organic acids such as amino acids, acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and others are
known to those of ordinary skill in the art. The pharmaceutically
acceptable salts of the present invention can be synthesized from the
parent active agent which contains a basic or acidic moiety by
conventional chemical methods. Lists of other suitable salts are found in
Remington's Pharmaceutical Sciences, 17th. ed., Mack Publishing
Company, Easton, Pa., 1985, the relevant disclosure of which is hereby
incorporated by reference.

[0104] The phrase "pharmaceutically acceptable" is employed herein to
refer to those compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.

[0105] As used herein, the term "patient" or "subject" are taken to mean
warm blooded animals such as mammals, for example, cats, dogs, mice,
guinea pigs, horses, bovine cows, sheep and humans.

[0106] A formulation of the invention can comprise an active agent present
in an effective amount. By the term "effective amount", is meant the
amount or quantity of active agent that is sufficient to elicit the
required or desired response, or in other words, the amount that is
sufficient to elicit an appreciable biological response when administered
to a subject.

[0107] The formulation of the invention can be used to deliver one or more
different active agents. Particular combinations of active agents can be
provided by the present formulation. Some combinations of active agents
include: 1) a first drug from a first therapeutic class and a different
second drug from the same therapeutic class; 2) a first drug from a first
therapeutic class and a different second drug from a different
therapeutic class; 3) a first drug having a first type of biological
activity and a different second drug having about the same biological
activity; 4) a first drug having a first type of biological activity and
a different second drug having a different second type of biological
activity. Exemplary combinations of active agents are described herein.

[0108] When combinations of active agents are used, one or both of the
active agents can be present in a sub-therapeutic amount. As used herein,
a sub-therapeutic amount is that amount of first drug that provides less
than a normal therapeutic response in patient to which the first drug is
administered in the absence of the second drug of the combination. In
other words, the first and second drugs may together provide an enhanced,
improved, additive or synergistic therapeutic benefit as compared to the
administration of each drug alone, i.e., in the absence of the other
drug.

[0109] Following its preparation, the SAE-CD composition can be included
in any known pharmaceutical formulation or dosage form. The compositions
and formulations of the invention are suitable for administration to a
subject by any means employed in the pharmaceutical industry. Exemplary
modes of administration include, without limitation, endobronchial
(intrapulmonary, intratracheal, intraaveolar), oral, peroral, ocular,
ophthalmic, otic, sublingual, buccal, transdermal, transmucosal, rectal,
vaginal, uterine, urethral, intrathecal, nasal, parenteral,
intraperitoneal, intramuscular, and subdermal administration.

[0110] A dosage form is available in a single or multiple dose form
containing among other things a quantity of active ingredient and the
SAE-CD composition, said quantity being such that one or more
predetermined units of the dosage form are normally required for a single
therapeutic administration. In the case of multiple dose forms, such as a
scored tablet, said predetermined unit will be one fraction such as a
half or quarter of the multiple dose form. It will be understood that the
specific dose level for any patient will depend upon a variety of factors
including the indication being treated, active agent employed, the
activity of active agent, severity of the indication, patient health,
age, sex, weight, diet, and pharmacological response, the specific dosage
form employed and other such factors.

[0111] Following preparation of the SAE-CD composition, it can be used to
prepare a formulation wherein the SAE-CD composition is complexed with or
not complexed with an active agent. By "complexed" is meant "being part
of a clathrate or inclusion complex with", i.e., a complexed active agent
is part of a clathrate or inclusion complex with a cyclodextrin
derivative.

[0112] By active agent/CD complex is generally meant a clathrate or
inclusion complex of a cyclodextrin derivative and an active agent. The
ratio of active agent:CD present in the molecular complex can vary and
can be in the range of about 10 to about 0.1, on a molar basis. Thus, the
CD will generally be, but need not be, present in excess of the active
agent. The amount of excess will be determined by the intrinsic
solubility of the agent, the expected dose of the agent, and the binding
constant for inclusion complexation between the specific drug (agent) and
the specific CD derivative used. It should be noted that the cyclodextrin
derivative can be present in uncomplexed form and therefore in amounts
substantially in excess of the amount of active agent present. The weight
ratio or molar ratio of derivatized cyclodextrin to active agent can
exceed 100, 1000 or even more.

[0113] Under some conditions, the SAE-CD composition can form one or more
ionic bonds with a positively charged acid-ionizable compound. Therefore,
it is possible for a compound to be complexed by way of an inclusion
complex with the derivatized cyclodextrin and to be non-covalently but
ionically bound to the derivatized cyclodextrin.

[0114] Even though the SAE-CD composition can be the sole carrier or
excipient in a formulation, it is possible to add other carriers to the
formulation to further improve its performance.

[0115] The SAE-CD composition can be included in any formulation requiring
a derivatized cyclodextrin. An active agent included in the formulation
can be delivered according to a rapid, immediate, pulsatile, timed,
targeted, delayed and/or extended release formulation.

[0116] By "immediate release" is meant a release of an active agent to an
environment over a period of seconds to no more than about 30 minutes
once release has begun and release begins within no more than about 2
minutes after administration. An immediate release does not exhibit a
significant delay in the release of drug.

[0117] By "rapid release" is meant a release of an active agent to an
environment over a period of 1-59 minutes or 0.1 minute to three hours
once release has begun and release can begin within a few minutes alter
administration or after expiration of a delay period (lag time) after
administration.

[0118] An extended release formulation containing the SAE-CD composition
will release drug in an extended manner. Mechanisms employed for such
delivery can include active agent release that is pH-dependent or
pH-independent; diffusion or dissolution controlled; pseudo-zero order
(approximates zero-order release), zero-order, pseudo-first, order
(approximates first-order release), or first-order; or rapid, slow,
delayed, timed or sustained release or otherwise controlled release. The
release profile for the active agent can also be sigmoidal in shape,
wherein the release profile comprises an initial slow release rate,
followed by a middle faster release rate and a final slow release rate of
active agent. As used herein, the term "extended release" profile assumes
the definition as widely recognized in the art of pharmaceutical
sciences. An extended release dosage form will release drug at
substantially constant rate over an extended period of time or a
substantially constant amount of drug will be released incrementally over
an extended period of time. The term "extended release", as regards to
drug release, includes the terms "controlled release", "prolonged
release", "sustained release", or "slow release", as these terms are used
in the pharmaceutical sciences. A controlled release can begin within a
few minutes after administration or after expiration of a delay period
(lag time) after administration. An extended release can begin within a
few minutes after administration or after expiration of a delay period
(lag time) after administration.

[0119] By "controlled release" is meant a release of an active agent to an
environment over a period of about eight hours up to about 12 hours, 16
hours, 18 hours, 20 hours, a day, or more than a day. By "sustained
release" is meant an extended release of an active agent to maintain a
constant drug level in the blood or target tissue of a subject to which
the device is administered. A controlled release can begin within a few
minutes after administration or after expiration of a delay period (lag
time) alter administration.

[0120] A timed release dosage form is one that begins to release drug
after a predetermined period of time as measured from the moment of
initial exposure to the environment of use.

[0121] A slow release dosage form is one that provides a slow rate of
release of drug so that drug is released slowly and approximately
continuously over a period of 3 hr, 6 hr, 12 hr, 18 hr. a day, 2 or more
days, a week, or 2 or more weeks, for example.

[0122] A targeted release dosage form generally refers to an oral dosage
form that designed to deliver drug to a particular portion of the
gastrointestinal tract of a subject. An exemplary targeted dosage form is
an enteric dosage form that delivers a drug into the middle to lower
intestinal tract but not into the stomach or mouth of the subject. Other
targeted dosage forms can delivery to other sections of the
gastrointestinal tract such as the stomach, jejunum, ileum, duodenum,
cecum, large intestine, small intestine, colon, or rectum.

[0123] A pulsatile release dosage form is one that provides pulses of high
active ingredient concentration, interspersed with low concentration
troughs. A pulsatile profile containing two peaks may be described as
"bimodal".

[0124] A pseudo-first order release profile is one that approximates a
first order release profile. A first order release profile characterizes
the release profile of a dosage form that releases a constant percentage
of an initial drug charge per unit time.

[0125] A pseudo-zero order release profile is one that approximates a
zero-order release profile. A zero-order release profile characterizes
the release profile of a dosage form that releases a constant amount of
drug per unit time.

[0127] The extended release layer can be a matrix diffusion, erosion,
dissolution, or disintegration-controlled composition comprising a drug
and one or more release rate modifying excipients and other optional
excipients.

[0128] By "delayed release" is meant that initial release of drug from a
respective drug-containing layer occurs after expiration of an
approximate delay (or lag) period. For example, if release of drug from
the extended release layer is delayed two hours, then release of drug
from that layer begins at about two hours after administration of the
multi-layered tablet to a subject. In general, a delayed release is
opposite an immediate release, wherein release of drug begins after no
more than a few minutes after administration. Accordingly, the drug
release profile from a particular layer can be a delayed-extended release
or a delayed-rapid release. A "delayed-extended" release profile is one
wherein extended release of drug begins after expiration of an initial
delay period. A "delayed-rapid" release profile is one wherein rapid
release of drug begins after expiration of an initial delay period.

[0129] Although not necessary, a formulation of the present invention can
include antioxidants, acidifying agents, alkalizing agents, buffering
agents, solubility-enhancing agents, penetration enhancers, electrolytes,
fragrances, glucoses, glidants, stabilizers, bulking agents,
cryoprotectants, plasticizers, flavors, sweeteners, surface tension
modifiers, density modifiers, volatility modifiers, hydrophilic polymers,
preservatives, antibacterial agents, colorants, antifungal agents,
complexation enhancing agents, solvents, salt, water, tonicity modifiers,
anti foaming agents, oil, penetration enhancers, other excipients known
by those of ordinary skill in the art for use in pharmaceutical
formulations, or a combination thereof. Upon each occurrence, these
materials can be independently included in the active agent-containing
particles or the carrier particles. For example, the carrier might
include one or more of these materials and the active agent-containing
particles might also include one or more of these materials.

[0130] As used herein, the term "glidant" is intended to mean an agent
used to promote flowability of the dry powder. Such compounds include, by
way of example and without limitation, magnesium stearate, sodium
dodecylsulfate, colloidal silica, cornstarch, talc, calcium silicate,
magnesium silicate, colloidal silicon, silicon hydrogel and other
materials known to one of ordinary skill in the art.

[0131] As used herein, the term "antioxidant" is intended to mean an agent
that inhibits oxidation and thus is used to prevent the deterioration of
preparations by the oxidative process. Such compounds include, by way of
example and without limitation, acetone, potassium metabisulfite,
potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,
butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate,
sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde
sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite
and others known to those of ordinary skill in the art.

[0132] As used herein, the term "alkalizing agent" is intended to mean a
compound used to provide alkaline medium when the dry powder of the
invention is exposed to water. Such compounds include, by way of example
and without limitation, ammonia solution, ammonium carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium borate,
sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine,
diethanolamine, organic amine base, alkaline amino acids and trolamine
and others known to those of ordinary skill in the art.

[0133] As used herein, the term "acidifying agent" is intended to mean a
compound used to provide an acidic medium when the dry powder of the
invention is exposed to water. Such compounds include, by way of example
and without limitation, acetic acid, acidic amino acids, citric acid,
fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic
acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and
others known to those of ordinary skill in the art.

[0135] A complexation-enhancing agent is a compound, or compounds, that
enhance(s) the complexation of an active agent with the derivatized
cyclodextrin. When the complexation-enhancing agent is present, the
required ratio of derivatized cyclodextrin to active agent may need to be
changed such that less derivatized cyclodextrin is required. Suitable
complexation enhancing agents include one or more pharmacologically Inert
water soluble polymers, hydroxy acids, and other organic compounds
typically used in liquid formulations to enhance the complexation of a
particular agent with cyclodextrins. Suitable water soluble polymers
include water soluble natural polymers, water soluble semisynthetic
polymers (such as the water soluble derivatives of cellulose) and water
soluble synthetic polymers. The natural polymers include polysaccharides
such as inulin, pectins, algin derivatives and agar, and polypeptides
such as casein and gelatin. The semi-synthetic polymers include cellulose
derivatives such as methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl
methylcellulose and other mixed ethers such as hydroxyethyl
ethylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl
methylcellulose phthalate and carboxymethylcellulose and its salts,
especially sodium carboxymethylcellulose. The synthetic polymers include
polyoxyethylene derivatives (polyethylene glycols) and polyvinyl
derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene
sulfonate) and various copolymers of acrylic acid (e.g. carbomer).
Suitable hydroxy acids include by way of example, and without limitation,
citric acid, malic acid, lactic acid, and tartaric acid and others known
to those of ordinary skill in the art.

[0136] As used herein, the term "preservative" is intended to mean a
compound used to prevent the growth of microorganisms. Such compounds
include, by way of example and without limitation, benzalkonium chloride,
benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium
chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric
nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma
picolinium chloride, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl,
propyl, or butyl parabens and others known to those of ordinary skill in
the art.

[0138] As used herein, the term "tonicity modifier" is intended to mean a
compound or compounds that can be used to adjust the tonicity of the
liquid formulation. Suitable tonicity modifiers include glycerin,
lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol,
trehalose and others known to those or ordinary skill in the art.

[0139] As used herein, the term "anti foaming agent" is intended to mean a
compound or compounds that prevents or reduces the amount of foaming that
forms on the surface of the fill composition. Suitable antifoaming agents
include by way of example and without limitation, dimethicone,
simethicone, octoxynol and others known to those of ordinary skill in the
art.

[0141] Other suitable polymers are well-known excipients commonly used in
the field of pharmaceutical formulations and are included in, for
example, Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R.
Gennaro (editor), Mack Publishing Company, Easton, Pa., 1990, pp.
291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical
Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd
edition (Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T.
Florence and D. Altwood, (Physicochemical Principles of Pharmacy, 2nd
Edition, MacMillan Press, London, 1988, pp. 281-334. The entire
disclosures of the references cited herein are hereby incorporated by
references. Still other suitable polymers include water-soluble natural
polymers, water-soluble semi-synthetic polymers (such as the
water-soluble derivatives of cellulose) and water-soluble synthetic
polymers. The natural polymers include polysaccharides such as inulin,
pectin, algin derivatives (e.g. sodium alginate) and agar, and
polypeptides such as casein and gelatin. The semi-synthetic polymers
include cellulose derivatives such as methylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, their mixed ethers such
as hydroxypropyl methylcellulose and other mixed ethers such as
hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose,
hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and
its salts, especially sodium carboxymethylcellulose. The synthetic
polymers include polyoxyethylene derivatives (polyethylene glycols) and
polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and
polystyrene sulfonate) and various copolymers of acrylic acid (e.g.
carbomer). Other natural, semi-synthetic and synthetic polymers not named
here which meet the criteria of water solubility, pharmaceutical
acceptability and pharmacological inactivity are likewise considered to
be within the ambit of the present invention. A solubility-enhancing
agent can be added to a formulation of the invention.

[0142] A solubility-enhancing agent is a compound, or compounds, that
enhance(s) the solubility of active agent in an aqueous or moist
environment, such as the lining of respiratory tract. Suitable solubility
enhancing agents include one or more organic solvents, detergents, soaps,
surfactants and other organic compounds typically used in parenteral
formulations to enhance the solubility of a particular agent. Suitable
organic solvents include, for example, ethanol, glycerin, poly(ethylene
glycols), propylene glycol, poly(propylene glycols), poloxamers, and
others known to those of ordinary skill in the art.

[0143] As used herein, the term "cryoprotectant" is intended to mean a
compound used to protect an active agent from physical or chemical
degradation during lyophilization. Such compounds include, by way of
example and without limitation, dimethyl sulfoxide, glycerol, trehalose,
propylene glycol, polyethylene glycol, and others known to those of
ordinary skill in the art.

[0144] Plasticizers can also be included in the preparations of the
invention to modify the properties and characteristics thereof. As used
herein, the term "plasticizer" includes all compounds capable of
plasticizing or softening a polymer or binder used in invention. The
plasticizer should be able to lower the melting temperature or glass
transition temperature (softening point temperature) of the polymer or
binder. Plasticizers, such as low molecular weight PEG, generally broaden
the average molecular weight of a polymer in which they are included
thereby lowering its glass transition temperature or softening point.
Plasticizers also generally reduce the viscosity of a polymer. It is
possible the plasticizer will impart some particularly advantageous
physical properties to the osmotic device of the invention. Plasticizers
useful in the invention can include, by way of example and without
limitation, low molecular weight polymers, oligomers, copolymers, oils,
small organic molecules, low molecular weight polyols having aliphatic
hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol),
multi-block polymers, single block polymers, low molecular weight
poly(ethylene glycol), citrate ester-type plasticizers, triacetin,
propylene glycol and glycerin. Such plasticizers can also include
ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene
glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and
other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl
ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether,
diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl
lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate,
triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl
glycolate. All such plasticizers are commercially available from sources
such as Aldrich or Sigma Chemical Co. It is also contemplated and within
the scope of the invention, that a combination of plasticizers may be
used in a formulation of the invention. The PEG based plasticizers are
available commercially or can be made by a variety of methods, such as
disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical
Applications (J. M. Harris, Ed.; Plenum. Press, NY) the disclosure of
which is hereby incorporated by reference.

[0145] As used herein, the term "flavor" is intended to mean a compound
used to impart a pleasant flavor and often odor to a pharmaceutical
preparation. Exemplary flavoring agents or flavorants include synthetic
flavor oils and flavoring aromatics and/or natural oils, extracts from
plants, leaves, flowers, fruits and so forth and combinations thereof.
These may also include cinnamon oil, oil of wintergreen, peppermint oils,
clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil,
oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other
useful flavors include vanilla, citrus oil, including lemon, orange,
grape, lime and grapefruit, and fruit essences, including apple, pear,
peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so
forth. Flavors which have been found to be particularly useful include
commercially available orange, grape, cherry and bubble gum flavors and
mixtures thereof. The amount of flavoring may depend on a number of
factors, including the organoleptic effect desired. Flavors will be
present in any amount as desired by those of ordinary skill in the art.
Particularly flavors are the grape and cherry flavors and citrus flavors
such as orange.

[0146] As used herein, the term "sweetener" is intended to mean a compound
used to impart sweetness to a preparation. Such compounds include, by way
of example and without limitation, aspartame, dextrose, glycerin,
mannitol, saccharin sodium, sorbitol, fructose, high fructose corn syrup,
maltodextrin, sucralose, sucrose, other materials known to one of
ordinary skill in the art, and combinations thereof.

[0147] As used herein, a penetration enhancer is an agent or combination
of agents that enhances penetration of an active agent through tissue.
Penetration enhancers which can be included in a formulation of the
invention include, by way of example and without limitation, calcium
chelators such as EDTA, methylated P-cyclodextrin, and polycarboxylic
acids; surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate,
carnitine, carnitine esters, and tween; bile salts such as sodium
taurocholate; fatty acids such as oleic and linoleic acid; and
non-surfactants such as AZONE'' and dialkyl sulfoxides; E-flux inhibitors
such as AV171 (AyMax, Inc., South San Francisco, Calif.).
D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and
peppermint oil; chitosan and chitosan derivatives such as N-methyl
chitosan, N-trimethyl chitosan, mono-N-carboxymethyl chitosan,
quaternized chitosan derivatives; SNAC (N-(8-(2-hydroxybenzoyl)amino)
caprylate) and SNAD (N-(10-(2-hydroxybenzoyl)amino)-decanoate) (Emisphere
Technologies. Inc., Tarrytown, N.Y.); N-acylated non-alpha amino acids:
HEMISPHERE brand delivery agents: Gelucire 44/14 or Vitamin E TPGS
CARBOPOL® 934P; others known to those of ordinary skill in the art;
and combinations thereof.

[0148] As used herein, a fragrance is a relatively volatile substance or
combination of substances that produces a detectable aroma, odor or
scent. Exemplary fragrances include those generally accepted as FD&C.

[0149] A "surface tension modifier" is a material or combination of
materials capable of modifying the surface properties of a composition
according to the invention. A surface tension modifier can include a
surfactant, detergent or soap. It can be included in the carrier
particles, the active agent-containing particles or both. A "density
modifier" is a material or combination of materials that is included in a
composition of the invention to increase or decrease the density thereof.
It can be included in the carrier particles, the active agent-containing
particles or both.

[0150] A density modifier can be used to increase or decrease (as needed)
the density of the carrier in order enhance dispersion of the active
agent from the carrier. Likewise, a density modifier can be used to
decrease or increase, respectively, (as needed) the density of the active
agent containing particles.

[0151] A "volatility modifier" is a material or combination of materials
added to modify the volatility of an active agent. In one embodiment, the
volatility modifier increases the volatility of the active agent. In
another, embodiment, the volatility modifier decreases the volatility of
the active agent.

[0152] As used herein, the term "stabilizer" is intended to mean a
compound used to stabilize the therapeutic agent against physical,
chemical, or biochemical process that would reduce the therapeutic
activity of the agent. Suitable stabilizers include, by way of example
and without limitation, albumin, sialic acid, creatinine, glycine and
other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide,
sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene
glycols, sodium caprylate and sodium saccharin and other known to those
of ordinary skill in the art.

[0153] As used herein, the term "bulking agent" is intended to mean a
compound used to add bulk to the lyophilized product and/or assist in the
control of the properties of a formulation during lyophilization. Such
compounds include, by way of example and without limitation, dextran,
trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol,
dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others
known to those of ordinary skill in the art.

[0154] It should be understood that compounds used in the art of
pharmaceutical formulations generally serve a variety of functions or
purposes. Thus, if a compound named herein is mentioned only once or is
used to define more than one term herein, its purpose or function should
not be construed as being limited solely to that named purpose(s) or
function(s).

[0155] In view of the above description and the examples below, one of
ordinary skill in the art will be able to practice the invention as
claimed without undue experimentation. The foregoing will be better
understood with reference to the following examples that detail certain
procedures for the preparation of compositions and formulations according
to the present invention. All references made to these examples are for
the purposes of illustration. The following examples should not be
considered exhaustive, but merely illustrative of only a few of the many
embodiments contemplated by the present invention.

Example 1

[0156] Exemplary formulations were made according to the following general
procedures.

Method A. Solid Formulation in Admixture.

[0157] A solid composition comprising cyclodextrin is mixed with a solid
composition comprising active agent until homogeneity. The
cyclodextrin-containing and active agent-containing compositions contain
less than about 20% wt. water. Mixing of the two compositions can also
include simultaneous attritting thereof or attrition can be performed as
a separate process step. For example, the cyclodextrin-containing
composition and the active agent-containing compositions are each
attritted separately prior to mixing. One or more additional excipients
can be included in the SAE-CD composition and/or the active agent
composition.

Method B. Liquid Formulation.

[0158] An SAE-CD composition is mixed with a liquid carrier optionally
containing an active agent. The SAE-CD composition can be mixed with the
liquid carrier either prior to, after or during addition oldie active
agent, if one is present. One or more other excipients can be included in
the formulation. If needed, heat can be applied to promote mixing or
dissolution.

Example 2

Preparation of SAE-CD Solid Compositions

[0159] In Methods A and B below, the SAE-CD starting material was provided
in an aqueous liquid carrier, and the SAE-CD starting material was
prepared according to a known literature method. Particular embodiments
included SAE-CD starling material dissolved in water. The concentration
of SAE-CD in the liquid carrier was varied as needed to provide a liquid
feed of the desired viscosity or solids content.

Method A. Fluidized Bed Spray Drying

[0160] An SAE-CD carrier was prepared by spray agglomeration in an FSD-16
fluid spray drier apparatus (GEA Niro Inc., Columbia Md.) as follows.
Several solutions of sulfobutyl ether-beta-cyclodextrin (degree of
substitution ˜7, SBE7-BCD) at 20.1-49.8% solids were agglomerated
in the FSD-16 using a top mounted Spraying Systems pressure nozzle at
atomization pressures of 1,500-2,000 psig and feed temperature
˜25° C. Process conditions were inlet/outlet temperatures of
210-250/83-100° C. fluid bed inlet temperatures of 80-100°
C., and fluid product bed temperatures of 67-87° C. Fines return
at the atomizer nozzle and at the chamber cone was investigated during
separate runs. The drying gas flows are heated electrically.

[0161] Feed solutions containing SAE-CD were prepared by adding powdered
constituents to the required amount of water under heat and agitation in
the feed tank.

Method B. Fluidized Bed Spray Drying

[0162] An SAE-CD composition was prepared by spray agglomeration in an
FSD-12.5 fluid spray drier apparatus (GEA Niro Inc., Columbia Md.) with
attached 3-chamber fluidization bed. The inner fluid bed chamber (chamber
1) was directly open to the drying chamber and was used for final
agglomeration, drying of agglomerates and dedusting. The outer ring fluid
bed chambers 2 and 3 are connected sequentially to chamber 1 such that
product moves from chamber 1 to chamber 2 to chamber 3 as controlled by
process conditions. Chamber 2 was used for post drying and continued
dedusting. Chamber 3 was used for cooling and final dedusting. The final
product was taken from chamber 3. The drying gas (N2) flows are heated
electrically and the main drying gas was introduced into the drying
chamber through a ceiling air disperser. The drying gas to the three
fluid bed chambers was evenly distributed across perforated plates. The
drying gas flows were individually adjusted to the different fluid bed
chambers.

[0163] Solutions of sulfobutyl ether-beta-cyclodextrin (degree of
substitution ˜7, SBE7-BCD) at 48-52% wt solids were agglomerated in
the FSD-12.5 using a top-mounted Spraying Systems pressure nozzle at
atomization pressures of 10-50 bar and a solution temperature of
45-55° C. Process conditions were inlet/outlet temperatures of
150-170/70-90° C., chamber 1 fluid bed inlet temperatures of
100-150° C., and chamber 1 product bed temperatures of
60-100° C. Fines were returned at a location adjacent the atomizer
nozzle.

Example 3

[0164] The particle diameter (size) distribution of several SAE-CD
compositions (sulfobutyl ether-beta-cyclodextrin, degree of substitution
˜7) was determined by laser diffraction (Malvern Instruments Inc,
Model 2000, South Borough, Mass.), equipped with a dry powder feeder
attachment. The dispersion pressure versus particle size curve was
generated and based upon a dispersion pressure of 60 psi. The powder was
sampled using 500 detector sweeps for statistical validity. The
obscuration values were monitored to ensure adequate data acquisition.
The 300 mm focal length detector lens was used, providing a size range of
5.8 to 564μ.

[0165] The particle size analysis data for exemplary SAE-CD compositions
of sulfobutyl ether-beta-cyclodextrin with an average degree of
substitution of ˜7, SBE7-BCD, is included in the table below. The
data for each composition indicate the particle diameters in microns
corresponding to the De Brouckere mean diameter (D|4,3|) or the particle
size cutoffs for the 10%, 50% or 90% cumulative volume fractions. (μ
is taken to mean micron.)

[0166] The moisture content of the SAE-CD compositions was measured via
the Karl Fisher method (USP<921>, Method 1a) or the moisture
balance method.

Moisture Balance Method

[0167] Computrac Model 200 XL moisture balance (Arizona Instruments,
Tempe, Ariz.) was used to determine the weight loss or selected powder
samples over time as the powder was exposed to infrared heating. The
powders were weighed (approximately 1 g for each sample), heated at
110° C. until no change in weight was observed, and the percentage
weight loss calculated.

Example 5

[0168] The flowability of solid SAE-CD compositions was determined with a
test apparatus (Flodex®, Hanson Research Corp., Northridge, Calif.)
having: [0169] A stainless steel cylinder with an approximate capacity
of 200 mL [0170] A series of stainless steel disks. Each disk having a
precise hole in the center in graduated sizes differing 1-2 mm in
diameter that is easily attached to form a bottom for the cylinder.
[0171] A shutter that covers the hole and that may be quickly removed
without vibration to allow the powder to flow through the selected hole.
[0172] An adjustable funnel for loading the sample cylinder with a free
fall of the test powder. [0173] A suitable container to collect the
powder that flows through the unit.

[0174] The funnel was mounted above the cylinder such that the bottom of
the funnel was near but not touching the powder surface once loaded into
the cylinder. A disk was inserted into the bottom of the cylinder and the
hole in the disk was closed. A powder load 25 of 50 g was then poured
through the funnel into the middle of the cylinder. The powder was
allowed to set in the cylinder for at least 30 seconds, then the hole in
the disk was opened quickly and without vibration. The flow through the
disk opening was then observed. A positive result was when the powder
flowed through the hole leaving a cavity shaped like an upside-down,
truncated cone in 3 of 3 trials and the powder that falls involves the
entire height of the powder (not less than 60 mm).

[0175] A negative result was noted when the powder fell abruptly through
the hole forming a cylindrical cavity in the remaining powder.

[0176] If the result was positive, the procedure was repeated with disks
having smaller diameter holes until the smallest diameter hole still
giving a positive result in 3 of 3 trials was determined.

[0177] If the result was negative, the procedure was repeated with disks
having larger diameter holes until the smallest diameter hole giving a
positive result in 3 of 3 trials was determined.

[0178] Results of the measurements for SAE-CD compositions (sulfobutyl
ether-beta-cyclodextrin with a degree of substitution of ˜7,
SBE7-B-CD) are given below.

[0179] The average dissolution time of SAE-CD compositions (sulfobutyl
ether-beta-cyclodextrin with an average degree of substitution ˜7,
SBE7-BCD) was determined by a flow-through dissolution device comprising
a glass filter holder (Millipore Corp., Billerica, Mass.) attached to a
pump and water reservoir. The filter holder was comprised of a ˜300
mL capacity funnel and a fritted glass base held together with a metal
clamp.

[0180] The test was conducted by placing a 2.5 g sample of the powder onto
a 47 mm×10 micron pore size filter mounted between the sections of
the filter holder. Water at ˜25° C. was pumped at a rate of
100 mL per minute through the bottom of the apparatus such that the water
would rise through the filter and into the reservoir. The sample was
observed to determine the time required for dissolution of all the
solids. If the sample floated and required longer than 2.5 minutes to
dissolve, the pump was stopped after delivering 250 mL.

[0181] Representative data for sulfobutyl ether-beta-cyclodextrin with an
average degree of substitution of 7 (SBE7-CD) are included in the table
below.

[0183] The powders were compressed on an instrumented Colton single
station press, running at 15 tablets per minute. The press had an
instrumented upper and lower punch compression force and displacement.
The sample weight was 200 mg and the samples were compressed to three
different tablet hardnesses of approximately 5, 10 and 15 kP using
flat-faced punches with a diameter of 0.345 inches. The force and
displacement data were collected using a 4-channel, 12-bit digital
oscilloscope (Model 420, Nicolet Instrument Corp., Madison, Wis., USA);
samples were collected every msec simultaneously for each of the four
channels. The die was lubricated with a 10% (w/v) slurry of magnesium
stearate in acetone applied with a cotton swab. To maintain
tablet-to-tablet consistency, a standardized procedure was developed for
swabbing and drying the slurry onto the die wall. The die-wall coverage
was also checked by visual inspection. To reduce signal noise, punch data
using Igor Pro version 3.1 (Wavemetrics, Inc., Oregon). The Igor Pro was
also used to find the Pmax in the average tablet pressure curve (i.e.,
maximum punch pressure) after the FFT had been performed: the software
algorithm found the minimum using the derivative of the curve.

[0184] Tablet breaking strength was measured with a KEY* HT-300 hardness
tester (Englishtown, N.J.). A dial indicator was used to measure post
compression tablet height. Typically, 5 tablets were compressed and
tested for hardness at each of the three target hardness levels.

Example 8

[0185] The density and compressibility of SAE-CD compositions was
determined by the following methods:

[0186] Method A. Bulk Density

[0187] Bulk density of SAE-CD compositions was determined according to USP
<616> Method I, using a 100 mL graduated cylinder.

[0193] The true density of SAE-CD compositions was determined with a
Multivolume Pycnometer (Micromeritics Instrument Corp., Model 1305,
Norcross, Ga.) according to the USP <699> method. A sample holder
having a one cm3 volume was used for all measurements.

[0194] The results of the measurements for SAE-CD compositions (sulfobutyl
ether-beta-cyclodextrin with and average degree of substitution ˜7.
SBE7-BCD, are given in the table below.

[0195] A dry powder formulation suitable for administration with a DPI
device comprises one or more active agents, SAE-CD composition carrier
and optionally one or more excipients selected from the group consisting
of an antioxidant, acidifying agent, alkalizing agent, buffering agent,
solubility-enhancing agent, penetration enhancer, electrolyte, fragrance,
glucose, glidant, stabilizer, bulking agent, cryoprotectant, plasticizer,
flavors, sweeteners, surface tension modifier, density modifier,
volatility modifier, or a combination thereof. The SAE-CD carrier
comprises about 50%-99.9% wt. of the formulation, and it has a median
particle diameter of less than 420 microns. The active agent-containing
particles have a median particle diameter between about 0.1 to 10
microns. The carrier has a span of about 1.5 to 2.9, and the carrier has
been made according to invention, and optionally attritting the solid to
form the particulate carrier. The SAE-CD used in the carrier has an
average DS in the range of about 1 to 12.

Example 10

[0196] A compressed rapid release tablet comprising sulfobutyl
ether-beta-cyclodextrin with an average degree of substitution of 4
(SBE4-1 CD, SAE-CD composition), and piroxicam is prepared according to
the following formula and procedure.

[0197] The above ingredients are used to make a 257 mg tablet core having
a rapid release profile. The numbers beside the ingredients indicates the
general order of addition. After each group of ingredients is added, the
mixture is dry blended for 5-10 min. The magnesium stearate, fumed
silicon dioxide (CABOSIL® M5P) and croscarmellose sodium are added in
separately (step 3) from other ingredients and an additional 5 min, dry
blend step is added to the general procedure.

[0198] The powder is then compressed to form a tablet with a hardness of
about 8-10 Kg.

Example 11

[0199] A controlled release tablet comprising an SAE-CD composition,
sulfobutyl ether-beta-cyclodextrin with an average degree of substitution
of 7 (SBE7-βCD), and prednisolone is prepared according to the
following formula and procedure.

[0200] The above ingredients are used to make a 300 mg tablet core having
a controlled release profile. The ingredients are blended by hand and
individual tablets are prepared on a carver press under a pressure of 1
ton for 7 seconds. The tablets are prepared using a 5/16'' standard cup
concave tooling.

Example 12

[0201] An orodispersable immediate release tablet comprising an SAE-CD
composition, sulfobutyl ether-gamma-cyclodextrin with an average degree
of substitution of 7 (SBE7-γCD), and zaleplon is prepared
according to the following formula and procedure.

[0202] All tablet ingredients are sieved through 40-mesh screen (US
Standard) prior to weighing, and then all ingredients except magnesium
(Mg) stearate are mixed in a glass bottle using a geometric dilution
technique. The powder blend is then passed through the 40-mesh screen
twice to facilitate homogenous mixing of all ingredients. Prior to
mechanical compression, Mg stearate is added and then mixed for an
additional minute. Lastly, the final blend is compressed into tablets
with 7-mm concave tooling using a rotary tablet press to give a tablet
hardness of approximately 3.0 kiloponds (kp).

Example 13

[0203] A constitutable powdered formulation of lamotrigine and a SAE-CD
composition, sulfobutyl ether-beta-cyclodextrin with an average degree of
substitution of 7 (SBE7βCD), was prepared using the following
formula.

[0204] The sodium saccharin, benzoic acid, strawberry flavor, citric acid,
and xanthan gum are combined together and mixed well. The lamotrigine is
added to the blend with further mixing then the SBE7-βCD is
added and mixing is continued. The xylitol is then added to the resulting
powder with geometric dilution and further mixing.

[0205] The powder can be constituted with water to give a final volume of
750 mL.

[0207] As used herein, the term "about" means +/-10% of the value
indicated.

[0208] The above is a detailed description of particular embodiments of
the invention. It will be appreciated that, although specific embodiments
of the invention have been described herein for purposes of illustration,
various modifications may be made without departing from the spirit and
scope of the invention. Accordingly, the invention is not limited except
as by the appended claims. All of the embodiments disclosed and claimed
herein can be made and executed without undue experimentation in light of
the present disclosure. The disclosure of any patent or other publication
cited herein is incorporated herein by reference.